Water-soluble polymer alkanals
View Patent ↗The present invention is directed to alkanal derivatives of water-soluble polymers such as poly(ethylene glycol), their corresponding hydrates and acetals, and to methods for preparing and using such polymer alkanals. The polymer alkanals of the invention are prepared in high purity and exhibit storage stability.
1. A polymer having the structure:
wherein:
POLY is a water-soluble polymer segment;
X′ is a linker moiety,
z′ is an integer from 3 to about 21;
R 1 , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl;
R 2 , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl,
W a and W b are each independently O or S, and
R 3 and R 4 are each independently H, or an organic radical selected from the group consisting of methyl, ethyl, isopropyl, benzyl, 1,1,1-trichloroethyl, and nitrobenzyl, or when taken together, are —(CH 2 ) 2 — or —(CH 2 ) 3 —, forming a 5 or 6 membered ring when considered together with W a , C 1 , and W b .
2. The polymer of claim 1 , wherein the following apply:
when POLY is linear:
(a) then the total number of carbonyls present in said polymer is 0 or 2 or greater except when X′ comprises one or more contiguous (—CH 2 CH 2 O—) segments,
(b) and further wherein X′ is oxygen or comprises at least one (—CH 2 CH 2 O) segment and z′ is from 3 to 12, then at least one of R 1 or R 2 in at least one occurrence is an organic radical as defined above or said polymer is heterobifunctional, where POLY comprises a reactive group at one terminus that is not hydroxy, and
when POLY is branched:,
(c) either at least one of R 1 or R 2 in at least one occurrence is an organic radical as defined above or X′ includes —(CH 2 CH 2 O) b — where b is from 1 to about 20
in the instance where POLY comprises a lysine residue,
(d) and further wherein POLY has 2 polymer arms, then neither polymer arm comprises oxygen as the only heteroatom in the instance where POLY comprises “C—H” as a branch point.
3. A water-soluble polymer having the structure:
wherein:
POLY is a water-soluble polymer segment;
X′ is a linker moiety,
z′ is an integer from 3 to about 21,
W a and W b are each independently O or S, and
R 3 and R 4 are each independently H, or an organic radical selected from the group consisting of methyl, ethyl, isopropyl, benzyl, 1,1,1-trichloroethyl, and nitrobenzyl, or when taken together, are —(CH 2 ) 2 — or —(CH 2 ) 3 —, forming a 5 or 6 membered ring when considered together with W a , C 1 , and W b .
4. The polymer of claim 3 , wherein said polymer is absent detectable amounts of iodine-containing species or retro-Michael-type reaction products.
5. The polymer of claim 1 , wherein z′ is an integer from 3 to 12.
6. The polymer of claim 5 , wherein z′ is selected from the group consisting of 3, 4, 5, 6, 7, and 8.
7. The polymer of claim 1 , wherein R 1 and R 2 in each occurrence is independently H or lower alkyl.
8. The polymer of claim 7 , wherein said lower alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl.
9. The polymer of claim 1 , where POLY is a linear, terminally end-capped water-soluble polymer segment.
10. The polymer of claim 1 , wherein POLY is selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyol).
11. The polymer of claim 1 , wherein POLY is a poly(alkylene oxide).
12. The polymer of claim 11 , wherein POLY is a poly(ethylene glycol).
13. The polymer of claim 3 , wherein z′ is an integer from 3 to 12.
14. The polymer of claim 13 , wherein z′ is an integer from 3 to 8.
15. The polymer of claim 14 , wherein z′ is 3.
16. The polymer of claim 1 , wherein W a and Wa b are both O.
17. The polymer of claim 1 , wherein X′ comprises a moiety corresponding to the structure:
—(CH 2 ) c -D e -(CH 2 ) f — or —(CH 2 ) p -M r -C(O)—K s —(CH 2 ) q —
wherein:
c is zero to 8,
D is O, NH, or S,
e is 0, 1
f is zero to 8,
p is zero to 8,
M is —NH, O
K is NH, O
q is from zero to 8, and
r and s are each independently 0, 1.
18. The polymer of claim 1 , wherein X′ is hydrolytically stable.
19. The polymer of claim 1 , wherein POLY corresponds to the structure:
Z-(CH 2 CH 2 O) n —CH 2 CH 2 —,
X′ is O
n is from about 10 to about 4000, and
Z is a moiety selected from the group consisting of hydroxy, ester, carbonate, aldehyde, alkenyl, acrylate, methacrylate, acrylamide, sulfone, thiol, carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, alkoxy, benzyloxy, silane, phospholipid, biotin, and fluorescein.
20. The polymer of claim 19 , wherein Z is C1 to C20 alkoxy or benzyloxy.
21. The polymer of claim 20 , wherein Z is methoxy.
22. The polymer of claim 12 , wherein said poly(ethylene glycol) has a structure selected from the group consisting of linear, branched and forked.
23. The polymer of claim 12 , wherein X′ includes an oligomeric moiety corresponding to the structure —(CH 2 CH 2 O) b — or —(CH 2 CH 2 NH) g —, and b and g are each independently 1 to 20.
24. The polymer of claim 23 , wherein b and g are each independently 1 to 10.
25. The polymer of claim 24 , wherein b and g are each independently 1 to 6.
26. The polymer of claim 15 , wherein X′ includes an oligomeric moiety corresponding to the structure —(CH 2 CH 2 O) b — or —(CH 2 CH 2 NH) g —, and b and g are each independently 1 to 20.
27. The polymer of claim 26 having the structure:
wherein said oligomeric moiety is covalently attached to the C4 methylene.
28. The polymer of claim 27 , wherein said X′ further comprises an amide or a urethane.
29. The polymer of claim 28 , wherein X′ is a moiety selected from the group consisting of —C(O)NH—(CH 2 CH 2 O) b —, —OC(O)NH—(CH 2 CH 2 O) b —, —C(O)NH—(CH 2 CH 2 NH) g —, —OC(O)NH—(CH 2 CH 2 NH) g —, and band g are as defined in claim 26 above.
30. The polymer of claim 1 , wherein X′ has an overall length of from about 1 to about 20 atoms.
31. The polymer of claim 30 , wherein X′ has an overall length of from about 2 to about 15 atoms.
32. The polymer of claim 1 , wherein R 3 and R 4 are the same.
33. The polymer of claim 12 , wherein said polyethylene glycol has a nominal average molecular mass of from about 100 daltons to about 100,000 daltons.
34. The polymer of claim 33 , wherein said polyethylene glycol has a nominal average molecular mass of from about 1,000 daltons to about 50,000 daltons.
35. The polymer of claim 1 , wherein said polymer is homobifunctional.
36. The polymer of claim 29 , wherein POLY is polyethylene glycol.
37. The polymer of claim 36 , wherein said polyethylene glycol is linear or branched.
38. The polymer of claim 37 , wherein said polyethylene glycol has a structure corresponding to:
wherein n in each occurrence is independently from about 10 to about 4000, and Z is a moiety selected from the group consisting of hydroxy, ester, carbonate, aldehyde, alkenyl, acrylate, methacrylate, acrylamide, sulfone, thiol, carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, alkoxy, benzyloxy, silane, phospholipid, biotin, and fluorescein.
39. The polymer of claim 38 , wherein said polyethylene glycol has a structure corresponding to:
Z is methoxy, and X′ is —C(O)NH—(CH 2 CH 2 O) b —.
40. The polymer of claim 39 , having the structure: